Search

The discovery of cancer stem cells (CSCs) fundamentally advanced our understanding of the mechanisms governing breast cancer development. However, the stimuli that control breast CSC self-renewal and differentiation have still not been fully detailed. We previously showed that nerve growth factor (NGF) and its precursor proNGF can stimulate breast cancer cell growth and invasion in an autocrine manner. In this study, we investigated the effects of NGF and proNGF on the breast CSC compartment and found that NGF or proNGF enrich for CSCs in several breast cancer cell lines. This enrichment appeared to be achieved by increasing the number of symmetric divisions of quiescent/slow-proliferating CSCs. Interestingly, in vitro NGF pretreatment of MCF-7 luminal breast cancer cells promoted epithelial to mesenchymal transition in tumors of severe combined immunodeficient mice. Furthermore, p75NTR, the common receptor for both neurotrophins and proneurotrophins, mediated breast CSC self-renewal by regulating the expression of pluripotency transcription factors. Our data indicate, for the first time, that the NGF/proNGF/p75NTR axis plays a critical role in regulating breast CSC self-renewal and plasticity. S tem C ells 2015;33:342-353 [ABSTRACT FROM AUTHOR]

Highlights: [•] The p75 neurotrophin receptor (p75NTR) undergoes sequential proteolytic cleavages in MDA-MB-231breast cancer cells. [•] The carboxyl-terminal fragment (p75NTR-CTF) but not the intracellular domain (p75NTR-ICD) is able to promote cell survival. [•] p75NTR-CTF favors cell survival independently of PI3-kinase, NF-κB, or MAP kinase signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: The p75 neurotrophin receptor (p75NTR) plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation and proliferation. To evaluate the influence of p75NTR in breast cancer development, we have established and characterized breast cancer cells which stably overexpress p75NTR. We showed that p75NTR overexpression per se promoted cell survival to apoptogens with a concomitant slowdown of cell growth. The pro-survival effect is associated with an increased expression of the inhibitor of apoptosis protein-1 (c-IAP1), a decrease of TRAIL-induced cleavage of PARP, procaspase 9 and procaspase 3, and a decrease of cytochrome C release from the mitochondria. The anti-proliferative effect is due to a cell accumulation in G0/G1, associated with a decrease of Rb phosphorylation and an increase of p21waf1. Interestingly, inhibition of p21waf1 with siRNA not only restores proliferation but also abolishes the pro-survival effect of p75NTR, indicating the key role of p21waf1 in the biological functions of p75NTR. Finally, using a SCID mice xenograft model, we showed that p75NTR overexpression favors tumor growth and strongly increases tumor resistance to anti-tumoral treatment. Together, our findings suggest that p75NTR overexpression in breast tumor cells could favor tumor survival and contribute to tumor resistance to drugs. This provides a rationale to consider p75NTR as a potential target for the future design of innovative therapeutic strategies. [Copyright &y& Elsevier]

Tremendous data have been accumulated in the effort to understand chemoresistance of triple negative breast cancer (TNBC). However, modifications in cancer cells surviving combined and sequential treatment still remain poorly described. In order to mimic clinical neoadjuvant treatment, we first treated MDA-MB-231 and SUM159-PT TNBC cell lines with epirubicin and cyclophosphamide for 2 days, and then with paclitaxel for another 2 days. After 4 days of recovery, persistent cells surviving the treatment were characterized at both cellular and molecular level. Persistent cells exhibited increased growth and were more invasive in vitro and in zebrafish model. Persistent cells were enriched for vimentinhigh sub-population, vimentin knockdown using siRNA approach decreased the invasive and sphere forming capacities as well as Akt phosphorylation in persistent cells, indicating that vimentin is involved in chemotherapeutic treatment-induced enhancement of TNBC aggressiveness. Interestingly, ectopic vimentin overexpression in native cells increased cell invasion and sphere formation as well as Akt phosphorylation. Furthermore, vimentin overexpression alone rendered the native cells resistant to the drugs, while vimentin knockdown rendered them more sensitive to the drugs. Together, our data suggest that vimentin could be considered as a new targetable player in the ever-elusive status of drug resistance and recurrence of TNBC. [ABSTRACT FROM AUTHOR]